Retroviruses, long associated with leukemia and sarcoma of animals, have recently been implicated as the etiological agents of human T cell leukemia and human acquired immune dificiency syndrome (AIDS). The identification of these agents makes it possible to consider various ways of prevention. The most promising approach is development of a vaccine that could be administered to individuals at risk. Friend leukemia virus complex is a useful model system, since it produces an acute disease in adult mice which can be prevented by repeated immunization with the envelope glycoprotein. The envelope (env) gene from Friend murine leukemia virus (F-MuLV) was inserted into the genome of a vaccinia virus expression vector. Infected cells synthesized pg85, the glycosylated primary product of the env gene. Processing to gp70 and p15E, and cell surface localization, were similar to that occurring in F-MuLV infected cells. Mice that were inoculated with the live recombinant viccinia virus had an envelope-specific T cell proliverative response and following challenge with FV complex developed neutralizing antibody and cytotoxic T cells (CTL) and were protected against leukemia. In contrast, unimmunized and control groups developed a delayed neutralizing antibody response but no detectable CTL and succumbed to leukemia. Genes of the major histocompatibility complex (H-2) influenced protection induced by the vaccinia recombinant but not that induced by attenuated N-tropic Friend virus. A similar approach was used to insert the env gene of the AIDS virus into the genome of vaccina virus. Formation of the gp160 precursor and processing to gp120 and gp41 occurred as in cells infected with AIDS virus. Furthermore, mice inoculated with the recombinant virus developed antibodies to gp120.